Circadian

Rhythm, Sleep, &

Mood
Brandon S. Lu, M.D., M.S.
Conflict of Interest
• None
• Circadian Biology
• Circadian Rhythm Sleep-Wake Disorders
• Circadian Rhythm and Mood
Biological Rhythms
• Many biological functions exhibit cycles which repeat each day,
month, or year. These cycles do not reflect simply an organism’s
passive response to environmental changes, such as the light-dark
cycle. Instead, they reflect an organism’s biological rhythms which are
endogenous rhythms that persist in the absence of any
environmental stimuli
Biological Periodicity
• 1 sec. Cardiac • 24 hr. Circadian Sleep-Wake
• 6 sec. Respiratory • 28 day Menstrual
• 90 min. Sleep stage • 365 day Circannual Hibernation
Circadian Rhythms
• A biological rhythm that has an endogenous free-running period of
about 24 hours
• When isolated from time cues such as sunlight, most creatures show
intrinsic rhythms of close to, but rarely exactly, 24 hours
• Circadian = circa (“about”) + dies (“a day”)
The first demonstration of a circadian rhythm by Jean Jacques d’Ortous
de Mairan in 1729
General Properties of Circadian Rhythms
• Circadian rhythms are generated by an internal clock or pacemaker.
Therefore, they persist in the absence of cues indicating the time or
length of the day.
• The internal clock that regulates circadian rhythms is synchronized, or
entrained to the light-dark cycle and other social and environmental
cues.
• These entraining agents can actually reset or phase shift circadian
rhythms. Depending on the time of exposure to these entraining
agents, circadian rhythms may be delayed or advanced.
 Circadian Rhythm of Temperature

Krauchi and Wirz-Justice. Am J Physiol 1994.

 Circadian Rhythm of Cortisol

Debono et al., J Clin Endocrinol Metab 2009.

Circadian Sleep-Wake
Rhythm
The Circadian Timing System
• The suprachiasmatic nucleus
(SCN) contains the master
circadian clock Light Output Rhythms
Physiology
• 3 components: Behavior
• Stimuli that entrain the pacemaker
• The pacemaker itself
• Output rhythms of the clock
Suprachiasmatic
Nuclei (SCN)
 The Circadian Timing System
• The suprachiasmatic nucleus
(SCN) contains the master
circadian clock
• 3 components:
• Stimuli that entrain the pacemaker Squirrel
Monkey
• The pacemaker itself
• Output rhythms of the clock
• Circadian rhythms are abolished
with complete lesions of the SCN

Albers et al., Neurosci Lett 1981.

Discovery of Clock gene
• ENU mutagenesis screen
• Clock, mouse chromosome 5,
human chromosome 4
• Semidominant
• Heterozygotes: circadian period
lengthened
• Homozygotes: rhythm abolished

Vitaterna et al., Science 1994

 Generation of Circadian Rhythms

Clock and Bmal are transcription factors that drive loop forward
Reppert and Weaver, Nature 2002
 Clocks Everywhere

Gerber et al., Diabetes Obes Metab 2015

Hastings et al., Nature Review 2003
Circadian Rhythm of Pulmonary Function in Healthy
Subjects
• 10 healthy subjects
• Constant routine for 41 hours
• Significant circadian variation in FEV1
and FEV1/FVC
• Circadian minima occurred during usual
sleep period

Spengler and Shea, Am J Respir Crit Care Med 2000

Circadian Rhythm Sleep-Wake Disorders
• Misalignment between an individual’s sleep pattern with that which is
desired or considered societal norm
• Due to 1) alteration in the circadian timing system or 2) a
misalignment between endogenous circadian rhythms and external
factors that affect the timing of sleep
Light Output Rhythms
Physiology
Behavior

Suprachiasmatic
Nuclei (SCN)
Lu and Zee. Chest 2006
Circadian Rhythm Sleep-Wake Disorders
16:00 20:00 24:00 04:00 08:00 12:00 16:00

Advanced Sleep-Wake Phase

Typical Sleep-Wake Phase

Delayed Sleep-Wake Phase

Irregular Sleep-Wake
Rhythm

Non-24 Hour Sleep-Wake

Rhythm
 Delayed Sleep-Wake Phase Disorder
• Presentation:
• Habitual sleep-wake timing that is delayed by more than 2 hours relative to
conventional timing
• Patients report difficulty falling asleep; once asleep, normal duration
• Difficulty arising at socially acceptable time
• Estimated prevalence of 0.17% in the general population (7% - 16% among
adolescents and young adults)
• Etiology:
• Polymorphism in the circadian clock gene hPer3
• Alterations in sensitivity to light
• Social and behavioral factors (school avoidance, social maladjustment, mood
disorder, etc.)

International Classification of Sleep Disorders, 3rd edition. 2014.

 Phase Response Curves to Light and to
Melatonin
Delays Advances 2
Phase Shift (hours)
Light

Melatonin

-2

-12 -8 -4 0 4 8 12
Circadian Time
Minors et al, Neurosci Lett, 1991
Lewy et al., Chronobiol Int, 1998
Noon 15 18 21 MN 3 6 9 Noon

Advanced
Sleep Phase

Normal Sleep Phase

Delayed
Sleep Phase

Noon 15 18 21 MN 3 6 9 Noon
Circadian Rhythm and Mood Disorder
• Circadian disruption is common in psychiatric disorders (sleep-wake
timing, body temperature rhythm, melatonin/cortisol secretion)
• Causal?
• Result of behavior leading to rhythm desynchronization?
• Overlap in molecular machinery and neural circuitry of psychiatric illness and
circadian system?
• Major depressive disorder is associated with late chronotype (β = .10,
P=.004)
• n=1,944 (676 currently depressed/anxious pts, 831 remitted pts, 437 controls)
• Clinical interviewed diagnosed mood disorder; Munich Chronotype
Questionnaire

Hasler et al., Psychiatry Res, 2010. Antypa et al, Depress Anxiety, 2016.
Jones and Benca. Sleep Med Clin, 2015.
Delayed Sleep-Wake Phase Disorder and
Mood Disorder

Reid et al., Sleep Med 2012.

Melatonin Rhythm and Depression
• Delayed rhythm associated
with worsening depression
• Correlation remained
significant if sleep items
were removed from HAM-D
• 18 women; average HAM-D=
15.9 ± 4.6

Emens et al. Psychatry Res 2009.

Melatonin/Sleep Rhythm and Depression
• 14 MDD and 13 controls (mean
age 40)
• HAM-D: 21 ± 4 vs. <1
• BDI: 25 ± 7 vs. <1
Control
• MDD had later sleep onset
(p<0.001), sleep midpoint
(p=0.02), and DLMO (p=0.09) MDD
• DLMO-CBTmin phase angles
significantly correlated with 18 20 22 24 2 4 6 8
HAM-D (rs=0.002, p=0.006)

Hasler et al., Psychiatry Res. 2010

Circadian genetics and mood disorders
• Psychiatric disorders are polygenic
• Environmental contribution
• Diagnoses are heterogeneous
• Single-nucleotide polymorphisms of clock genes (CLOCK, PER2, PER3,
CRY1, CRY2, etc.) are associated with mood disorders such as major
depressive disorder and bipolar disorder

Etian et al., Eur Neuropsychopharmacol 2011.

Soria et al., Neuropsychopharmacology 2010.
Circadian Gene Expression in Major
Depressive Disorder
• Loss of rhythmicity of core clock gene expression in major depressive
disorder compared to controls
• Anterior cingulate (ACC), dorsolateral prefrontal cortex, hippocampus,
amygdala, nucleus accumbens and cerebellum
• Postmortem tissue
• 55 control, 34 MDD

Li et al, Proc Natl Acad Sci 2013.

Treatment of Depression with Chronotherapy
• Light therapy for depression is effective and has similar effect size as
pharmacologic therapies (0.53 – 0.84)
• Besides circadian effects, light has independent effects on sleep, mood,
alertness, cognition, etc.
• Sleep deprivation and sleep phase
advancement are similarly effective for
depression

Golden et al, Am J Psychiatry 2005.

Berger et al., Am J Psychiatry, 1997.
Treatment of Depression with Chronotherapy

Echizenya et al., J Affect Disord 2013

Treatment of Depression with Chronotherapy
• Wake therapy (sleep deprivation), bright light therapy, and sleep time
stabilization
• Duloxetine + wake/bright light/sleep stabilization vs. duloxetine +
exercise
• 1-week inpatient intervention
• Wake therapy Mon, Wed, Fri
• Daily morning bright light therapy (10,000 lux) for 30 minutes
• Stable sleep-wake schedule to prevent oversleeping
• Minimum of 30 minute exercise daily
• 7-week continuation phase
Martiny et al., J Clin Psychiatry 2012.
Treatment of Depression with Chronotherapy

Martiny et al., J Clin Psychiatry 2012.

Treatment of Depression with Chronotherapy

Response Rate at week 9:

- Wake therapy: 71.4%
- Exercise: 47.3% (p = 0.04)
Remission Rate at week 9:
- Wake therapy: 45.6%
- Exercise: 23.1% (p = 0.04)

Martiny et al., J Clin Psychiatry 2012.

Summary
• Many physiological processes have circadian rhythms
• SCN is the master circadian clock that synchronizes peripheral
rhythms
• Phase advancement of delayed sleep-wake phase disorder patients
with morning bright light and evening melatonin
• Evidence implicates circadian rhythm abnormalities contribute to
mood disorders (genetic polymorphism, desynchrony of internal
rhythms)
• “Chronotherapy” may improve major depressive disorder